Synthesis and In Vitro Evaluation of Novel Nortropane Derivatives as Potential Radiotracers for Muscarinic M_2 Receptors

• Published in: International Journal of Molecular Imaging Vol. 2011; pp. 286 - 292
• Main Authors: Knol, Remco J. J., van den Bos, Jan C., Janssen, Anton G. M., de Bruin, Kora, van Eck-Smit, Berthe L. F., Booij, Jan
• Format: Journal Article
• Language: English
• Published: Hindawi Limiteds 01.12.2011
• ISSN: 2090-1712; 2090-1720
• DOI: 10.1155/2011/709416

Disturbances of the cerebral cholinergic neurotransmitter system are present in neurodegenerative disorders. SPECT or PET imaging, using radiotracers that selectively target muscarinic receptor subtypes, may be of value for in vivo evaluation of such conditions. 6 β -acetoxynortropane, a potent muscarinic M 2 receptor agonist, has previously demonstrated nanomolar affinity and high selectivity for this receptor. Based on this compound we synthesized four nortropane derivatives that are potentially suitable for SPECT imaging of the M 2 receptor. 6 β -acetoxynortropane and the novel derivatives were tested in vitro for affinity to the muscarinic M 1−3 receptors. The original 6 β -acetoxynortropane displayed high affinity ( K i = 70 – 90  nM) to M 2 receptors and showed good selectivity ratios to the M 1 (65-fold ratio) and the M 3 (70-fold ratio) receptors. All new derivatives showed reduced affinity to the M 2 subtype and loss of subtype selectivity. It is therefore concluded that the newly synthesized derivatives are not suitable for human SPECT imaging of M 2 receptors.